The present invention relates to novel compounds that are positive allosteric AMPA receptor modulators, processes for preparing them and their use, as pharmaceutical compositions, in the treatment of various disease conditions.
The compounds according to the invention are compounds of general formula (I) 
wherein
A denotes a sulphur atom, oxygen atom, NH or Nxe2x80x94C1-C4-alkyl,
R1 denotes a group selected from among hydrogen, a C1-C6-alkyl group optionally substituted by one or more halogen atoms, xe2x80x94SO2H, xe2x80x94SO2xe2x80x94C1-C6-alkyl, xe2x80x94SOxe2x80x94C1-C6-alkyl, xe2x80x94COxe2x80x94C1-C6-alkyl, xe2x80x94O, phenyl-C1-C4-alkyl, xe2x80x94C1-C4-alkyl-NR7R8,
xe2x80x94C1-C4-alkyl-Oxe2x80x94C1-C4-alkyl and C3-C6-cycloalkyl,
R2, R9, which may be identical or different, denote a group selected from among hydrogen, a C1-C6-alkyl group optionally substituted by one or more halogen atoms, halogen, xe2x80x94NO2, xe2x80x94SO2H, xe2x80x94SO2xe2x80x94C1-C6-alkyl, xe2x80x94SOxe2x80x94C1-C6-alkyl, xe2x80x94COxe2x80x94C1-C6-alkyl, xe2x80x94OH, xe2x80x94Oxe2x80x94C1-C6-alkyl, xe2x80x94Sxe2x80x94C1-C6-alkyl, xe2x80x94C1-C4-alkyl-NR7R8 and xe2x80x94C1-C4-alkyl-Oxe2x80x94C1-C4-alkyl, C3-C6-cycloalkyl, or
R1 and R2 together denote a C2-C6-alkylene bridge,
R7, R8, which may be identical or different, denote hydrogen or C1-C4-alkyl, and
R3, R4, R5, R6, which may be identical or different, denote a group selected from among hydrogen, a C1-C6-alkyl group optionally substituted by one or more halogen atoms, phenyl-C1-C4-alkyl, halogen, xe2x80x94CN, xe2x80x94NO2, xe2x80x94SO2H, xe2x80x94SO3H, xe2x80x94SO2xe2x80x94C1-C6-alkyl, xe2x80x94SOxe2x80x94C1-C6-alkyl, xe2x80x94SO2xe2x80x94NR7R8, xe2x80x94COOH, xe2x80x94COxe2x80x94C1-C6-alkyl, xe2x80x94Oxe2x80x94COxe2x80x94C1-C4-alkyl, xe2x80x94COxe2x80x94Oxe2x80x94C1-C4-alkyl, xe2x80x94COxe2x80x94NR7R8, xe2x80x94OH, xe2x80x94Oxe2x80x94C1-C6-alkyl, xe2x80x94Sxe2x80x94C1-C6-alkyl, xe2x80x94NR7R8 and an aryl group optionally mono- or polysubstituted by halogen atoms, xe2x80x94NO2, xe2x80x94SO2H or C1-C4-alkyl,
optionally in the form of the various enantiomers and diastereomers thereof, as well as the pharmacologically acceptable salts thereof.
Compounds of general formula (I) are preferred wherein
A denotes a sulphur atom, oxygen atom or Nxe2x80x94C1-C2-alkyl,
R1 denotes a group selected from among hydrogen, a C1-C6-alkyl group optionally substituted by one or more halogen atoms, xe2x80x94SO2H, xe2x80x94SO2xe2x80x94C1-C6-alkyl, xe2x80x94SOxe2x80x94C1-C6-alkyl, xe2x80x94COxe2x80x94C1-C6-alkyl, xe2x80x94O, xe2x80x94C1-C4-alkyl-NR7R8 and xe2x80x94C1-C4-alkylxe2x80x94Oxe2x80x94C1-C4-alkyl, benzyl,
R2, R9, which may be identical or different, denote a group selected from among hydrogen, a C1-C6-alkyl group optionally substituted by one or more halogen atoms, halogen, xe2x80x94NO2, xe2x80x94SO2H, xe2x80x94SO2xe2x80x94C1-C6-alkyl, xe2x80x94SOxe2x80x94C1-C6-alkyl, xe2x80x94COxe2x80x94C1-C6-alkyl, xe2x80x94OH, xe2x80x94Oxe2x80x94C1-C6-alkyl, xe2x80x94Sxe2x80x94C1-C6-alkyl, xe2x80x94C1-C4-alkyl-NR7R8 and xe2x80x94C1-C4-alkyl-Oxe2x80x94C1-C4-alkyl, or
R1 and R2 together denote a C3-C6-alkylene bridge, and
R3, R4, R5, R6, which may be identical or different, denote a group selected from among hydrogen, a C1-C4-alkyl group optionally substituted by one or more halogen atoms, phenyl-C1-C4-alkyl, halogen, xe2x80x94CN, xe2x80x94NO2, xe2x80x94SO2H, xe2x80x94SO3H, xe2x80x94SO2CH3, xe2x80x94SOCH3, xe2x80x94COxe2x80x94C1-C4-alkyl, xe2x80x94OH, xe2x80x94Oxe2x80x94C1-C4-alkyl and xe2x80x94Sxe2x80x94C1-C4-alkyl,
optionally in the form of the various enantiomers and diastereomers thereof, as well as the pharmacologically acceptable salts thereof.
Compounds of general formula (I) are particularly preferred wherein
A denotes a sulphur atom or Nxe2x80x94C1-C2-alkyl,
R1, R2, R9, which may be identical or different, denote hydrogen, C1-C4-alkyl, benzyl or
R1 and R2 together denote a C3-C4-alkylene bridge, and R3, R4, R5, R6 , which may be identical or different, denote a group selected from among hydrogen, C1-C4-alkyl, CF3, NO2, benzyl, xe2x80x94SO2xe2x80x94C1-C4-alkyl, xe2x80x94SO3H and halogen, preferably fluorine, chlorine, bromine, most preferably fluorine or chlorine, optionally in the form of the various enantiomers and diastereomers thereof, as well as the pharmacologically acceptable salts thereof.
Also particularly preferred are compounds of general formula (I) wherein
A denotes a sulphur atom or Nxe2x80x94CH3,
R1, R2, R9 which may be identical or different, denote hydrogen, C1-C4-alkyl or
R1 and R2 together denote a C3-C4-alkylene bridge,
R3, R5, R6, which may be identical or different, denote a group selected from among hydrogen, C1-C4-alkyl and halogen, preferably fluorine, chlorine, bromine, most preferably fluorine or chlorine, and
R4 denotes hydrogen, halogen or C1-C4-alkyl,
optionally in the form of the various enantiomers and diastereomers thereof, as well as the pharmacologically acceptable salts thereof.
Of particular importance according to the invention are the compounds of general formula (I) wherein
R1 denotes methyl, ethyl, i-propyl, n-butyl or benzyl, optionally in the form of the various enantiomers and diastereomers thereof, as well as the pharmacologically acceptable salts thereof.
Particularly preferred are compounds of general formula (I), wherein
A denotes a sulphur atom,
R1 denotes methyl,
R2, R9 denote hydrogen,
R3 denotes a group selected from among hydrogen, methyl, CN and halogen, preferably fluorine, chlorine, bromine, most preferably fluorine or chlorine,
R5 denotes a group selected from among hydrogen, methyl and halogen, preferably fluorine, chlorine, bromine, most preferably fluorine or chlorine,
R4 denotes hydrogen, and
R6 denotes hydrogen or methyl, preferably hydrogen,
optionally in the form of the pharmacologically acceptable salts thereof.
Most particularly preferred are compounds of general formula (I), wherein
A denotes a sulphur atom,
R1 denotes methyl,
R3 denotes hydrogen, fluorine or chlorine, and
R2, R4, R5, R6, R9 denote hydrogen,
optionally in the form of the pharmacologically acceptable salts thereof.
The alkyl groups used, unless otherwise stated, are branched and unbranched alkyl groups having 1 to 6 carbon atoms, preferably I to 4 carbon atoms. Examples include: methyl, ethyl, propyl, butyl, pentyl and hexyl. The groups methyl, ethyl, propyl or butyl may optionally also be referred to by the abbreviations Me, Et, Prop or Bu. Unless otherwise stated, the definitions propyl, butyl, pentyl and hexyl also include all possible isomeric forms of the groups in question. Thus, for example, propyl includes n-propyl and iso-propyl, butyl includes iso-butyl, sec. butyl and tert.-butyl, etc.
In the abovementioned alkyl groups, one or more hydrogen atoms may optionally be substituted by the halogen atoms fluorine, chlorine, bromine or iodine. The substituents fluorine and chlorine are preferred. The substituent fluorine is particularly preferred. If desired, all the hydrogen atoms of the alkyl group may be replaced.
The alkyl group mentioned in the group phenyl-C1-C4-alkyl may be in branched or unbranched form. Unless otherwise stated benzyl and phenylethyl are preferred phenyl-C1-C4-alkyl groups. Benzyl is particularly preferred.
The C2-C6-alkylene bridge may, unless otherwise stated, be branched and unbranched alkylene groups having 2 to 6 carbon atoms, for example ethylene, propylene, methylethylene, dimethylmethylene, n-butylene, 1-methylpropylene, 2-methylpropylene, 1.1-dimethylethylene, 1 .2-dimethylethylene etc. n-Propylene and n-butylene bridges are particularly preferred.
The aryl group is an aromatic ring system having 6-10 carbon atoms, preferably phenyl. In the abovementioned aryl groups, one or more hydrogen atoms may optionally be substituted by halogen atoms, xe2x80x94NO2, xe2x80x94SO2H or xe2x80x94C1-C4-alkyl, preferably fluorine, chlorine, xe2x80x94NO2, ethyl or methyl, most preferably fluorine or methyl.
The term C3-C6-cycloalkyl denotes saturated cyclic hydrocarbon groups having 3-6 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
The term halogen, unless otherwise stated, refers to fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine, most preferably fluorine and chlorine, most preferably fluorine.
As already mentioned, the compounds of formula (I) or the various enantiomers and diastereomers thereof may be converted into the salts thereof, particularly for pharmaceutical use, into the physiologically and pharmacologically acceptable salts thereof. These salts may on the one hand take the form of physiologically and pharmacologically acceptable acid addition salts of the compounds of formula (I) with inorganic or organic acids. On the other hand, the compound of formula (I) where R1 is hydrogen may be converted by reaction with inorganic bases into physiologically and pharmacologically acceptable salts with alkali or alkaline earth metal cations as counter-ion. The acid addition salts may be prepared, for example, using hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid. It is also possible to use mixtures of the above acids. For preparing the alkali and alkaline earth metal salts of the compound of formula (I) wherein R1 denotes hydrogen, it is preferable to use the alkali and alkaline earth metal hydroxides and hydrides, the hydroxides and hydrides of the alkali metals, especially sodium and potassium, being preferred, while sodium and potassium hydroxide are particularly preferred.
The compounds according to the invention may be prepared in a manner known per se. The following general methods of synthesis shown in Diagrams 1 and 2 below are meant to illustrate the invention without restricting it to their content.
Method 1
Starting from a compound of formula (IV) a compound of formula (V) is prepared by sulphonation and subsequent chlorination. The compound of formula (VI) obtained after condensation with aminoacetic acid derivatives is cyclised by the addition of polyphosphoric acid to the target compound (I). Commercially unobtainable compounds of formula (IV) are prepared beforehand by converting the compounds of formula (II) into the compounds of formula (III), wherein R , R   which may be identical or different denote C1-C6-alkyl or together denote a 1,2-ethylene or 1,3-propylene group, and subsequently cyclising them under the effect of strong acids.
The general preparation of the compounds according to the invention as shown in Diagram 1 is hereinafter described in more detail with reference to the benzothiophene derivatives (A=S). The process can be carried out analogously with the corresponding indole or benzofuran derivatives:
Synthesis of the diethoxy-ethyl-thiophenols (III):
10 mmol of the thiophenol (II) are dissolved in 2-100 ml, preferably 3-20 ml, most preferably 4 ml of an alcohol, particularly methanol, and combined with 10-50 mmol, preferably 11-30 mmol, most preferably 12 mmol of an alkoxide solution, particularly a sodium ethoxide solution. After 20-120 min, preferably 30 min, 10-50 mmol, preferably 11-30 mmol, most preferably 12 mmol of bromoacetaldehyde dialkylacetal are added and the solution is heated for 2-16 h, preferably 5 h, to 20-100xc2x0 C., preferably 50-70xc2x0 C. After evaporation of the solution the residue is divided between an organic solvent and water, particularly taken up with 30 ml of ether and 30 ml of water. The phases are separated and the aqueous phase is then extracted with ether. The combined organic extracts are dried over sodium sulphate and evaporated down in vacuo. The crude product is used in the next reaction without further purification.
Instead of the solvent methanol it is also possible to use ethanol, tetrahydrofuran, toluene, benzene, dimethylformamide, trichloromethane, dichloromethane, acetone or ethyl acetate, instead of the sodium methoxide solution it is possible to use potassium hydroxide, potassium-tert. butoxide, lithium hydroxide, triethylamine, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), sodium hydride or potassium carbonate as the base.
Synthesis of the benzothiophenes (IV):
10-100 ml, preferably 30 ml, of polyphosphoric acid and 10-250 ml, preferably 40 ml, of chlorobenzene are taken at 140xc2x0 C. and 10 mmol of the dialkoxy-ethyl-thiophenol (III) are added. After 2-16 h, preferably 5 h, stirring at 90-160xc2x0 C., preferably 140xc2x0 C., the phases are separated and the inorganic phase is extracted with ether. The combined organic extracts are dried over Na2SO4 and evaporated down in vacuo. The residue is purified by distillation.
Instead of the polyphosphoric acid it is possible to use a mixture of phosphorus pentoxide/phosphoric acid and zinc chloride, while toluene or xylene may be used instead of chlorobenzene.
Sulphonation of the benzothiophenes (IV):
10 mmol of the benzothiophene derivative (IV) are dissolved in 2-100 ml, preferably 3-80 ml, most preferably 4 ml, of acetic anhydride and 10 to 100 mmol, preferably 11-80 mmol, most preferably 11 mmol, of conc. sulphuric acid are added dropwise at 0-50xc2x0 C., preferably 5-20xc2x0 C. After 2-16 h, preferably 5 h, stirring at 20-100xc2x0 C., preferably 25 Cxc2x0, the mixture is poured onto a saturated NaCl solution. The crystals formed are suction filtered and dried.
Instead of acetic anhydride it is possible to use methylene chloride, diisopropylether, ethyl acetate, trichloromethane, toluene, benzene or 1,4-dioxane, while oleum, sulphur trioxide, chlorosulphates or combinations thereof may be used instead of conc. sulphuric acid.
Synthesis of benzothiophene-3-sulphonic acid chlorides (V):
10 mmol of benzothiophene-3-sulphonic acids are combined successively with 10 to 500 mmol, preferably 90 mmol, of phosphorus oxytrichloride and 8-50 mmol, preferably 10 mmol of phosphorus pentachloride and heated for 2-16 h, preferably 5 h, at 20-100xc2x0 C., preferably by refluxing. The reaction mixture is then evaporated down in vacuo and ice water is added. After extraction with ether the combined organic extracts are dried with disodium sulphate and the solvent is eliminated in vacuo. The crude product obtained is used in the following steps without purification.
Instead of the mixture of phosphorus oxytrichloride/phosphorus pentachloride, it is also possible to use thionyl chloride, phosphorus pentachloride, a mixture of phosphoric acid/chlorine or phosgene. The reaction may alternatively be carried out in the diluents ethyl acetate, water, acetonitrile, N,N-dimethylacetamide, sulpholane, DMF, hexane or dichloroethane.
Synthesis of the benzothiophene-3-sulphonyl-amino-acetic acids:
10 mmol of the chlorosulphonyl-benzothiophenes, 10-100 mmol, preferably 11-30 mmol, most preferably 12 mmol, of aminoacetic acid and 10-100 mmol, preferably 11-30 mmol, most preferably 12 mmol, of sodium hydroxide are dissolved in 16 ml of water and 16 ml of toluene. The reaction mixture is stirred for 2-16 h at 0-110xc2x0 C., preferably at 65xc2x0 C., then the phases are separated. The aqueous phase is acidified with 2N hydrochloric acid and extracted with ethyl acetate. The combined organic extracts are dried over sodium sulphate and evaporated down in vacuo. The residue is purified by chromatography. Instead of sodium hydroxide it is possible to use triethylamine, potassium carbonate, sodium hydrogen carbonate or sodium hydride, while instead of toluene it is possible to use tetrahydrofuran, diethylether, dichloromethane, trichloromethane, dioxane, acetone, benzene, ethanol, methanol, ethyl acetate or acetonitrile.
Cyclisation of benzothiophene-3-sulphonyl-amino-acetic acids (VI):
10 mmol of the benzothiophene-3-sulphonyl-amino-acetic acids are combined with 10-200 g, preferably 40 g, of polyphosphoric acid and stirred for 2-16 h, preferably 5 h, at 20-110xc2x0 C., preferably 75-95xc2x0 C. Then the reaction mixture is poured onto ice water and extracted with ethyl acetate. The combined organic extracts are dried over disodium sulphate and concentrated by evaporation. The residue is purified by chromatography.
Process 2
The compounds of formula (V) prepared as intermediate compounds in process 1 are reacted with primary amines to form the compounds of formula (VII) and then cyclised by the addition of a compound of formula R2R9Cxe2x95x90O in the presence of strong acid to form the target compounds (I).
Paraformaldehyde, trioxane or formalin may be used to prepare the compounds of formula (I) wherein R1 and R2 denote hydrogen, while methanesulphonic acid, trifluoroacetic acid, sulphuric acid, phosphoric acid or polyphosphoric acid may be used as strong acids.
The general preparation of the compounds according to the invention as shown in Diagram 2 is described hereinafter with reference to the benzothiophene derivatives (Axe2x95x90S). The process can be carried out analogously with the corresponding indole or benzofuran derivatives.
Synthesis of the benzothiophene-sulphonamides (VII):
10 mmol of the chloro-benzothiophene-sulphonic acids (V) are combined with an alcoholic solution of the primary amine (10-1000 mmol in 5-200 ml, for example 200 mmol in 50 ml ethanol) and then heated for 2-16 h, preferably 5 h at 0-100 Cxc2x0, preferably by refluxing. The reaction mixture is then evaporated down in vacuo and purified by chromatography.
Instead of the alcoholic solvent it is possible to use toluene, benzene, trichloromethane, dichloromethane, diethylether, tetrahydrofuran, water, acetonitrile, acetic anhydride, acetone, pyridine, dimethylsulphoxide, dimethylformamide, dioxane or hexane.
Cyclisation of the benzothiophene-sulphonamides (VII) into the target compounds (I):
10 mmol of the benzothiophene-sulphonamides are dissolved in 0-100 ml, preferably 20-80 ml, most preferably about 40 ml of methanesulphonic acid and combined with a solution of 3-50 mmol, preferably 4-30, most preferably 5 mmol of trioxane in 0-100 ml, preferably about 12 ml of trifluoroacetic acid. The reaction mixture is stirred for 2-16 h, preferably 5 h, at 20-100 Cxc2x0, preferably 30-80xc2x0 C., most preferably 35xc2x0 C. and then poured onto ice water. After extraction with ether and drying of the combined organic extracts over Na2SO4 the solution is concentrated by evaporation. The crude product is purified by chromatography.
Instead of trioxane it is possible to use paraformaldehyde or formalin, while instead of trifluoroacetic acid it is possible to use boron trifluoride*diethylether, acetic acid, polyphosphoric acid, phosphoric acid or sulphuric acid. Acetic anhydride or dichloromethane may be used as possible solvents. The new compounds of general formula (I) may be synthesised analogously to the following examples of synthesis. However, these Examples are intended solely as examples of procedure to illustrate the invention, without restricting it to their content.
Synthesis of 4-methyl-4,5-dihydro-1,3-dithia-4-aza-acenaphthylene 3,3-dioxide